Ali Shahbazi

The effect of leptin on prepulse inhibition in a developmental model of schizophrenia.

Post-weaning social isolation is a developmental animal model of schizophrenia. Impairment of prepulse inhibition (PPI), possibly due to increased activity of the mesolimbic dopaminergic system, has frequently been reported in this model. There are some reports of increased level of leptin in schizophrenic patients. It has been shown that intracerebroventricular (ICV) injection of leptin decreases dopamine in the nucleus accumbens of rats. Here we investigated the effect of leptin on PPI impairment following social isolation. Five groups of Sprague-Dawley rats were reared post weaning in social or isolated conditions for 14 weeks. PPI was measured before treatment in week 12, and after ICV injection of vehicle or different doses of leptin (1, 5, and 10μg/5μl) in week 14. Results showed reduced PPI in untreated isolated compared to socially-reared rats in week 12 (p=0.009), but not in week 14 (p=0.45). Results also showed that leptin dose-dependently increased the basal PPI in isolated rats compared to vehicle, that was significant at a dose of 10μg (p=0.002). A considerable but non-significant effect of treatment with leptin on startle response (p=0.13) was seen. In conclusion, our results reveal that leptin significantly increases PPI in socially-isolated rats. The findings of this study suggest possible antipsychotic properties for leptin. We suggest further studies on the possible disruption of leptin signaling in schizophrenia, and also the possible interaction of leptin with therapeutic effects of second generation antipsychotics.

Anticonvulsant activity of the ethanolic extract of Punica granatum L. seed

Abstract Objective: Various morphological parts of pomegranate (Punica granatum L.) have extensively been used in the folk medicine to treat an array of human ailments. The aim of the present study is to demonstrate the anticonvulsant potential of the ethanolic extract of P. granatum L. seed in chemoconvulsant-induced seizures in mice. Method: The anticonvulsant activity of the ethanolic extract was investigated in strychnine (STR)-induced and pentylenetetrazole (PTZ)-induced seizure models in mice. Diazepam was used as reference anticonvulsant drug. Ethanolic extract (150, 300, and 600 mg/kg per os, p.o.), diazepam (1 mg/kg intraperitoneally, i.p.), and distilled water (10 ml/kg, i.p.) were administered before induction of seizures by PTZ (60 mg/kg, i.p.) or STR (2·5 mg/kg, i.p.). The latent time before the onset of convulsions, the duration of convulsions, the percentage of seizure protection, and mortality rate were recorded. Results: The seed ethanolic extract did not show any toxicity and did not protect the animals against seizures but demonstrated a significant increase in seizure latency at 300 and 600 mg/kg in both STR and PTZ seizure models (P < 0·001). It also showed a significant reduction in seizure duration at 300 mg/kg (P < 0·05) and 600 mg/kg (P < 0·001) in the STR seizure model and 600 mg/kg (P < 0·01) in the PTZ seizure model compared with the control group. Conclusion: Ethanol extract has dose-dependent anticonvulsant activity against STR- and PTZ-induced seizures. This activity might be due to its saponins, flavonoids, triterpenes, and alkaloids ingredients.

Human erythropoietin effect in postoperative visual loss following spine surgery: a case report.

Introduction: Postoperative visual loss (POVL) has become the focus of attention for anesthesiologists as a hallmark of perioperative management in spine surgery. A number of Intraoperative and postoperative factors has been documented but the exact etiology is still unclear. Nowadays, perioperative management and also complete curing of POLV is a big question of ophthalmologists and anesthesiologists. The purpose of this case report is to present a unique experience of complete curing the POLV. Case Presentation: Our patient was a 61-year-old man, with 75 kg weight and 180 cm height. The patient had no history of visual impairment except mild cataract in his right eye. The patient had a history of diffuse idiopathic skeletal hyperostosis (DISH). The patient had undergone lumbar surgery in prone position. The operation time was about 6 hours. About 30 minutes after transferring to postanesthesia care unit (PACU), patient was awake and complained of losing his eyesight. There was no vision and light perception in his right eye on primary examination. Urgent ophthalmologist consultation was requested. In ophthalmology examinations, the pupil reflex to light was absent in the right eye. After obtaining patients and his family informed consent, four hours after the operation, 40000 I.U. of recombinant human erythropoietin (rhEPO) was administered for patient in PACU (IV infusion, in 30 min). An ophthalmologist visited him every 6 hours after administration of rhEPO. The patient was transferred to intensive care unit (ICU) one hour later with total visual loss in the right eye. Ophthalmologic examination after the second dose of rhEPO, 30 hours after the operation, reported pupil reflex enhancement and light perception in his right eye. Finally the third dose of rhEPO (40000 I.U., IV infusion) was administered on the third day. Ophthalmologic examination after the third dose of rhEPO, 60 hours after the operation, reported normal pupillary light reflex of the right eye and visual acuity improvement to 20/20. The patient was discharged from hospital after six days, with normal visual acuity and without any new complications except surgical site pain. Conclusions: Our case report showed the therapeutic effect of rhEPO in complete curing of POVL. Regarding the side effects of EPO such as thrombogenic effects or mild hemodynamic changes like transient sinus tachycardia during infusion, it seems that beneficial effects of EPO is more than its disadvantages and expenses, for patients with POVL.

The Effect of Luteinizing Hormone Reducing Agent on Anxiety and Novel Object Recognition Memory in Gonadectomized Rats

Introduction: Mood disorders such as anxiety and depression are common following menopause and andropause. Lack of sex steroid hormones is suggested as the primary cause of these disturbances. The level of luteinizing hormone (LH) would also rise 3–4 times than normal in these people. The potential effects of LH on mood and cognitive symptoms following menopause and andropause are still unknown. This study aimed to investigate the effect of increased LH on novel object discrimination (NOD) memory and anxiety like behavior in gonadectomized rats. Methods: Four-month-old male and female Wistar rats were randomly assigned into 4 groups (in each sex): control rats (Cont), gonadectomized without treatment (GnX), gonadectomized treated with triptorelin, a GnRH agonist which reduces LH release eventually, (GnX+Tr), gonadectomized treated with triptorelin plus sex steroid hormone, estradiol in female and testosterone in male rats (GnX+Tr+S/T). After 4 weeks treatment, anxiety score (elevated plus maze) and NOD were measured. Data were analyzed using One-way ANOVA, and P-values less than 0.05 were considered as significant. Results: Gonadectomy increased anxiety like behaviors (decrease of presence time in the open arms) in female rats (P=0.012), but not in male ones (P=0.662). Additionally, triptorelin alone reduced the increased anxiety score in gonadectomized female rats, compared to group treated with both triptorelin and estradiol. Furthermore, it was shown that gonadectomy and or treatment with triptorelin and sex steroids had no significant effect on novel object recognition memory in both female (P=0.472) and male rats (P=0.798). Conclusion: Findings of this study revealed that increased level of LH following menopause or andropause should be considered as a possible cause for increased anxiety. Also, this study showed that LH reducing agents would reduce anxiety like behavior in gonadectomized female rats. The effect of increased LH on cognitive functions such as novel object recognition memory was not evident in this study and needs further studies.

Effect of bumetanide, a selective NKCC1 inhibitor, on hallucinations of schizophrenic patients; a double-blind randomized clinical trial.

Hallucinations are a debilitating symptom of schizophrenia and can extremely influence the life quality of patients. A considerable percentage of schizophrenia patients suffer from hallucinations unresponsive to routine antipsychotics, which are called treatment-resistant hallucinations. Although the certain mechanisms responsible for hallucinations are poorly understood, subcortical dopaminergic dysregulation has been suggested to exert a pivotal role (Boksa, 2009). Recently, it has been highlighted that hippocampal overactivity might underlie the dopaminergic dysfunction of schizophrenia (Grace, 2012). Indeed, some postmortem studies revealed that the level of chlorideintruder Na-K-Cl cotransporter 1 (NKCC1) and chloride-extruder KCl cotransporter 2 (KCC2), two cation chloride cotransporters that determine gama-aminobutyric acid (GABA) mode of action through regulation of intercellular chloride concentration, is altered in hippocampal formation (Arion and Lewis, 2011; Hyde et al., 2011). As a result, hippocampal GABAergic function may be excitatory in schizophrenic patients. The diuretic bumetanide, a selective NKCC1 inhibitor, has been shown to effectively restore the inhibitory GABAergic function in neuropsychiatric disorders such as epilepsy and autism (Eftekhari et al., 2013; Lemonnier and Ben-Ari, 2010). A recent study reported that bumetanide abolished hallucinations in a case of schizophrenia (Lemonnier et al., 2016). Therefore, we aimed to investigate the efficacy and safety of bumetanide on refractory hallucinations of schizophrenic patients in a randomized double-blind placebo-controlled clinical trial. We enrolled 24 schizophrenia patients, according to DSM-IV, who had auditory hallucinations with severity of at least 4 on item P3 of PANSS and a certain documented history of treatment-resistance, which is defined as at least two adequate trials of antipsychotics for at least six weeks (Kinon et al., 1993) at 500 mg/day chlorpromazine equivalents for conventional neuroleptics and 6 mg/day risperidone, 15 mg/day olanzapine, or 400 mg/day clozapine for atypical antipsychotics (Dixon et al., 1995). Patients with a concurrent history of significant psychiatric (except schizophrenia) or medical disorders have been excluded. All patients and their families signed a written consent. One group (n = 12 per group) received bumetanide tablet 1 mg twice daily for two months and the other group received placebo instead. The observers and patients were blind to the treatment throughout the study. At the end, two patients of both groups have been excluded from the study. All the procedures and treatments were approved by the ethical committee of the University of social welfare and rehabilitation sciences with ethical number of USWR.REC.1392.47. This study

Lack of the effect of bumetanide, a selective NKCC1 inhibitor, in patients with schizophrenia: A double-blind randomized trial: Letter to the Editor

T HE EXCITATORY FUNCTION of GABA has been reported to contribute to the pathogenesis of some neuropsychological disorders, for example autism and epilepsy. The switch in GABA function, from inhibitory to excitatory, has been attributed to the alteration of cation-chloride cotransporters involved in the regulation of intercellular chloride concentration, chloride-intruder NKCC1 and chlorideextruder KCC2. A recent post-mortem study revealed that the NKCC1/KCC2 expression ratio is reduced in hippocampal formation of schizophrenic patients, which notably indicates that GABA may be excitatory in this region. In accordance, it has been suggested that hippocampal overactivity may underlie dopaminergic system dysregulation in cortical and subcortical regions. Bumetanide, a selective NKCC1 inhibitor, works as a potent agent for restoring the inhibitory function of GABA. Recently, the therapeutic effect of bumetanide in some neurological disorders, such as autism and epilepsy, has been shown. Thus, we designed a study to investigate the effect of bumetanide on patients with schizophrenia. The present study was registered in the official clinical trial registration system of the Iranian Health Ministry with registration number IRCT2014012616374N1. All of the procedures and treatments were approved by the local ethics committee of the University of Social Welfare and Rehabilitation Sciences with ethical number USWR. REC.1392.47. Twenty-six patients with schizophrenia were enrolled in this study. In summary, the diagnosis of schizophrenia, at any subtype, according to the DSM-IV, was the mainstay of patients’ enrollment and patients were excluded: (i) if they had a total score of <65 on the Positive and Negative Syndrome Scale (PANSS); (ii) if they had a documented fluctuation in symptoms; or (iii) if they had concurrent history of significant psychiatric disorder (except schizophrenia) or any other significant organ disorders. All patients and their families provided written consent. The experimental group (n = 14) received bumetanide tablet orally 1 mg twice daily while the control group (n = 12) received placebo in the same way. All patients were allowed to continue their routine antipsychotic drugs during the study. Duration of treatment was 2 months. For each group, the PANSS total score, PANSS subscores (Positive, Negative, and Cognitive), and the Brief Psychiatric Rating Scale (BPRS) total score were determined at the beginning, 1 and 2 months after treatment, and 1 month after a drug-free washout period (Table 1). Results of two-way repeated-measure analysis of variance revealed that in schizophrenic patients, treatment with bumetanide or placebo had no significant effect on: PANSS total score, F(1, 24) = 1.47, P = 0.236; PANSS Positive subscore, F(1, 24) = 0.012, P = 0.913; PANSS Negative subscore, F(1, 24) = 1.492, P = 0.234; or PANSS Cognitive subscore, F(1, 24) = 1.33, P = 0.259. Also, the effect of interaction of time and treatment on PANSS score was not significantly different, F(3, 72) = 0.098, P = 0.961. In addition, our results

Neuroprotective Effects of Exercise on Brain Edema and Neurological Movement Disorders Following the Cerebral Ischemia and Reperfusion in Rats

Introduction: Cerebral ischemia and reperfusion causes physiological and biochemical changes in the neuronal cells that will eventually lead to cell damage. Evidence indicates that exercise reduces the ischemia and reperfusion-induced brain damages in animal models of stroke. In the present study, the effect of exercise preconditioning on brain edema and neurological movement disorders following the cerebral ischemia and reperfusion in rats was investigated. Methods: Twenty-one adult male wistar rats (weighing 260–300 g) were randomly divided into three groups: sham operated, exercise plus ischemia, and ischemia group (7 rats per group). The rats in exercise group were trained to run on a treadmill 5 days a week for 4 weeks. Transient focal cerebral ischemia and reperfusion were induced by middle cerebral artery occlusion (MCAO) for 60 minutes, followed by reperfusion for 23 hours. After 24 hours ischemia, movement disorders were tested by a special neurological examination. Also, cerebral edema was assessed by determining the brain water content. Results: The results showed that pre-ischemic exercise significantly reduced brain edema (P<0.05). In addition, exercise preconditioning decreased the neurological movement disorders caused by brain ischemia and reperfusion (P<0.05). Conclusion: Preconditioning by exercise had neuroprotective effects against brain ischemia and reperfusion-induced edema and movement disorders. Thus, it could be considered as a useful strategy for prevention of ischemic injuries, especially in people at risk.

What do the genetic association data say about the high risk of suicide in people with depression? A novel network-based approach to find common molecular basis for depression and suicidal behavior and related therapeutic targets

BACKGROUND Available sources indicate that the risk of suicide in people with major depression is higher than other psychiatric disorders. Although it seems that these two conditions may have a shared cause in some cases, no studies have been conducted to identify a common basis for them. METHODS In this study, following an extensive review of literature, we found almost all the genes that are involved in major depression and suicidal behavior, and we isolated genes shared between the two conditions. Then, we found all physical or functional interactions within three mentioned gene sets and reconstructed three genetic interactive networks. All networks were analyzed topologically and enriched functionally. Finally, using a drug repurposing approach, we found the main available drugs that interacted with the most central genes shared between suicidal behavior and depression. RESULTS The results demonstrated that BDNF, SLC6A4, CREB1, and TNF are the most fundamental shared genes; and generally, disordered dopaminergic, serotonergic, and immunologic pathways in neuronal projections are the main shared deficient pathways. In addition, we found two genes, SLC6A4 and SLC6A2, to be the main therapeutic targets, and Serotonin-Norepinephrine Reuptake Inhibitors (SNRI) and Tricyclic Antidepressants (TCA) to be the most effective drugs for individuals with depression at risk for suicide. CONCLUSIONS Our results, in addition to shedding light on the integrated molecular basis of depression-suicide, offer new therapeutic targets for individuals with depression at high risk for suicide and could pave the way for future preclinical and clinical studies. However, integrative systems biology-based studies highly depend on existing data and related databases, as well as the arrival of new experimental data sources in the future, possibly affecting the current results.